T lymphocytes are tasked with ensuring host defense against a diverse array of pathogens. They must also maintain tolerance to self-antigens to avoid autoimmunity and allergic disease. To achieve these disparate tasks, the immune system relies on a complex system of T cell proliferation, differentiation and lineage commitment. As such, understanding the fundamental mechanisms that intrinsically regulate the fate and function of an individual T cell remain important questions in immunobiology. Accumulating evidence indicates that metabolism is an important intrinsic regulator of lymphocyte function and adaptive immunity. Perturbations in the metabolic state of lymphocytes can alter T effector/helper cell function, memory T cell generation and self-tolerance. Early studies on human lymphocytes demonstrated that mitogenic signaling results in a rapid increase in de novo cholesterol and fatty acid biosynthesis. The lipid biosynthetic program precedes DNA synthesis and appears to be essential for efficient lymphocyte growth. Importantly, inhibition of the lipogenic program decreases DNA synthesis and proliferative capacity of activated lymphocytes. The molecular mechanisms underlying these striking observations have remained undefined to date. In this application, we test the hypothesis that the Sterol Response Element Binding Proteins (SREBP1 and 2), key transcriptional regulators of lipid biosynthesis and homeostasis, play a critical role in linking antigen receptor signaling with lipid metabolism, cell cycle progression and T cell fate/function. Our aims are: 1) To define the signaling pathways regulating SREBP activity and de novo lipogenesis downstream of the antigen receptor; 2) To test the hypothesis that SREBP signaling regulates cell cycle progression in activated T cells; and 3) To test the hypothesis that SREBP regulates CD8 T cell responses and immunity. The proposed studies examine a very poorly understood and potentially important aspect of lymphocyte biology. It is our expectation that these studies will increase our understanding of the crosstalk between metabolism and adaptive immunity. These studies will provide a foundation for better understanding the relationship between lipid metabolism, proliferation and differentiation in rapidly dividing hematopoietic and immune cells. PUBLIC HEALTH RELEVANCE: An important goal of immunology is elucidating the mechanisms that regulate antigen-specific immunity and autoimmunity. The experiments outlined in this proposal integrate our understanding of T cell immunobiology with current ideas regarding molecular lipid metabolism. These studies will define the relative importance of transcriptional regulation of lipid metabolism on host defense and self-tolerance, as well as elucidate the signaling pathways downstream of the antigen receptor that coordinate the lipogenic program of lymphocytes. Moreover, these studies will provide a foundation for better understanding the potential influence of lipid metabolic programs on other rapidly proliferating normal and neoplastic tissue. Given that endogenous lipids can be altered in a number of human diseases, such as dyslipidemia and atherosclerosis, our results raise the interesting possibility that molecular metabolism may impact acquired immune responses in human metabolic diseases such as dyslipidemia, obesity, diabetes and metabolic syndrome.